Abstract

Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element–binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance.

Figure 5

(A) Western blot for carbohydrate responsive element–binding protein (ChREBP) in jejunal and liver whole-cell lysates of control (CTL) and intestine-specific ChREBP-KO (IChKO) mice. (B) Body weight and (C) food intake were measured in 6- to 8-week-old male and female control and IChKO mice fed high-fructose diet (HFrD) for 36 hours (n = 3 per group). (D) Eight-week-old female control and IChKO mice were fasted for 6 hours, and then gavaged with water or fructose and sacrificed 100 minutes later. Jejunal gene expression (n = 3 per group). (E) Representative images of small intestine and cecum in situ and (F) H&E–stained jejunal sections of control and IChKO after 36 hours of HFrD taken at ×10 magnification from mice described in B, as well as (G) serum TNF-α levels, (H) hepatic mRNA expression, and (I) serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. Data are presented as box-and-whisker plots where the line in the box indicates the median, the box extends from the 25th to 75th percentiles, and the whiskers indicate the minimal and maximal values. P values were obtained using 2-way ANOVA. *P < 0.05 compared between water and fructose within the same genotype; #P < 0.05 compared between different genotypes within the same treatment group.